Ca2+ sparks as the elementary intracellular Ca2+ release events are instrumental to local control of Ca2+ signaling in many types of cells. Ca2+-induced Ca2+ release (CICR) is a ubiquitous mechanism by which Ca2+ release from the endoplasmic reticulum amplifies the trigger Ca2+ entry and generates propagating Ca2+ waves. To elucidate the mechanisms that control this positive feedback, we investigated the spatial and temporal kinetics and measured the gain function of CICR in small sensory neurons from mammalian dorsal root ganglions (DRG). We found that subsurface Ca2+ release units (CRUs) are under tight local control by Ca2+ entry, whereas medullar CRUs as a ?common pool? system is recruited by inwardly propagating CICR. CICR in DRG neurons operates in a low-gain, linear regime (gain=0.54), which confers intrinsic stability to CICR. Combined with high Ca2+ current density (156pA/pF at ?10mV), such low-gain CICR system generated large intracellular Ca2+ transients without jeopardizing the stability. These findings provide the first demonstration that CICR operating in a low-gain regime can be harnessed to provide a robust and graded amplification of Ca2+ signal in the absence of counteracting termination mechanism. Furthermore, we visualized neural Ca2+ sparks in DRG sensory neurons and investigated possible role of DRG sparks in the regulation of secretion from the somata of the cell. DRG sparks arose mainly from type 3 ryanodine receptor Ca2+ release channels on subsurface cisternae of the endoplasmic reticulum, rendering a striking subsurface localization. Caffeine- or DMPX-induced store Ca2+ release, in the form of Ca2+ sparks, triggered exocytosis, independently of membrane depolarization and external Ca2+. The spark-secretion coupling probability was estimated to be between 1 vesicle/6.6 sparks to 1 vesicle/ 11.4 sparks. During excitation, subsurface sparks were evoked by physiological Ca2+ entry via the CICR mechanism, and their synergistic interaction with Ca2+ influx accounted for about 60% of the Ca2+-dependent exocytosis. Furthermore, inhibition of CICR abolished endotoxin-induced secretion of pain-related neuropeptides. These findings underscore an important role for Ca2+ sparks in the amplification of surface Ca2+ influx and regulation of neural secretion.